This generally relates to biodegradable polymers useful for medical applications, especially polyanhydrides having improved physicochemical properties.
Polyanhydrides are particularly useful as controlled release devices since they are biocompatible and degrade linearly by hydrolysis. Polyanhydrides of aromatic diacids offer several advantages over aliphatic polymers. They possess longer release and degradation times when used as degradable materials for drug release (Leong, et al., J. Biomed. Res. 19, 941, (1985)), possess high thermodynamic stability in solid state and organic solutions (A. Domb and R. Langer, Macromolecules, 22, 2117, (1989)), and are more favorable with respect to drug-polymer interactions, especially for proteins (Ron, et al., Proceed. Inter. Control Rel. Bioact. Mater., 16, (1989)). Aromatic and aliphatic diacids are acids where the carboxylic acid is connected to an aromatic ring or aliphatic residue, respectively.
Unfortunately, aromatic polyanhydrides have in general very low solubility in common organic solvents (less than 0.1% solubility in chlorinated, aromatic, or aliphatic hydrocarbons) and have high melting points, generally in excess of 200.degree. C., Encyclopedia of Polym. Sci. Tech., 10, 630 (1969) and references within). These properties limit the uses of aromatic polymers since they cannot be fabricated by either solvent techniques (fabrication into films or microspheres from solvents) due to their low solubility, nor using melt processing techniques due to their high melting point. Aromatic polymers are also usually highly crystalline, with the result that the polymers are characterized by brittleness and poor flexibility.
One way to overcome these limitations is by copolymerization of aromatic diacids with aliphatic diacids. The resulting copolymers have relatively low melting points, and increased mechanical strength as the aromatic content is increased (A. Domb and R. Langer, J. Polym. Sci. 25, 3373 (1987)). However, these copolymers also have the disadvantages of aliphatic polymers, e.g. hydrolytic and thermal instability, and copolymers containing more than 65% aromatic diacids are insoluble in common organic solvents and have high crystallinity and melting points.
Very little has been reported on the synthesis and properties of copolymers of aromatic diacids. Cottler and Matzner, reported in Chemich Weekblad, 63, 113 (1967), that insoluble copolymers of terephthalic and isophthalic acids had melting points in the range of 250.degree. to 315.degree. C. Several copolymers of terephthalic acid or isophthalic acid and nitrogen containing aromatic diacids were also reported that melted at temperatures above 200.degree. C., and were reported to be "soluble" in carbon tetrachloride, although no definition of the percent of solubility was given. There are no reports of a fully aromatic or even a copolymer of aromatic and aliphatic diacids of more than 70% aromaticity, which is soluble in chloroform or dichloromethane, has low crystallinity, and melts at a temperature below 200.degree. C.
The ideal polyanhydride would be one which possesses the properties of an aromatic polymer, good hydrolytic and thermodynamic stability and superior mechanical strength, yet is soluble in common organic solvents and melts at temperature below 200.degree. C.
It is therefore an object of the present invention to provide polyanhydride compositions with high aromatic content, of at least 70% aromatic diacid units, which are soluble in organic solvents such as dichloromethane or chloroform, melt at temperatures below 200.degree. C., and have low crystallinity.
It is another object of the present invention to provide polyanhydride compositions with high aromatic content which can be formulated into films or microspheres using solvent techniques, or which can be formulated into filaments or films by melt techniques for biomedical use.